γ-Amino butyric acid (GABA) is one of the major inhibitory neurotransmitters in the mammalian central nervous system. It plays the principal role in reducing neuronal excitability throughout the nervous system. GABA acts at inhibitory synapses in the brain by binding to specific transmembrane protein receptors in both pre- and post-synaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in stabilizing or causing hyperpolarization of the resting membrane potential. Two general classes of GABA receptor are known: 1) GABAA in which the ionotropic receptor is part of a ligand-gated ion channel complex, and 2) GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins). (WIKI).
GABA does not cross the blood brain barrier (BBB) efficiently and brain cells make nearly all of the GABA found in the brain by decarboxylation of glutamic acid with pyridoxal phosphate. The deficiency of GABA in the brain is associated with a number of neurological disease states. When the concentration of GABA falls below a threshold level, then seizures occur, which are stopped by raising the brain GABA concentration. Other neurological conditions such as schizophrenia, Huntington's chorea, motion disorders, Alzheimer's disease, depression, and anxiety are linked to low levels of GABA and the enzyme glutamic acid decarboxylase (GAD), (e.g., K. Gaicy, et al., Current Medicinal Chem., 2010, 17, 2338-2347; and numerous references cited therein).
Over the past half century or more, numerous GABA analogs with superior pharmacological properties have been synthesized, e.g., the classical discovery of baclofen; nipecotic acid, guvacine, and homo-β-proline. Commercially, gabapentin (cyclohexylgaba), and pregabalin (S-isobutylgaba) are hugely successful as add-on therapy for epilepsy, neuropathic pain, and fibromyalgia. All these compounds are lipophilic analogs of GABA, substituted at the central 3rd carbon of GABA to facilitate diffusion across the BBB. (Perumal Yogeeswari, et al., Recent Patents on CNS Drug Discovery, 2006, 1, 113-118). Both gabapentin and pregabalin have an affinity for the L-amino acid transporter which facilitates transport across the BBB of zwitterionic endogenous amino acids such as leucine, isoleucine, and valine. This mechanism also provides support in the transport of exogenous γ-amino acids, gabapentin, pregabalin and numerous other synthetic analogs.
Recently, vigabatrin was approved to treat complex epilepsy in adults and children. Vigabatrin is unique in that it is a specific, irreversible inhibitor of the enzyme γ-aminobutyric acid α-oxoglutarate transaminase (GABA-T), which use leads to beneficial long lived elevated GABA levels in the brain. Vigabatrin, (RS)-4-aminohex-5-enoic acid, is an unusual analog of GABA, in that it has unsaturation, a vinyl group, in the 4-position of GABA. Most GABA analogs have saturated, short hydrocarbon chains attached at the central 3rd carbon. The vinyl group in vigabatrin participates in the irreversible inhibition of the enzyme GABA-T, and sustains higher brain levels of GABA. (See WIKI for reaction mechanism). In contrast, recent discovery efforts have focused on conformationally constrained cyclopropyl β-amino acid analogs of pregabalin and gabapentin. These backbone-rigid analogs are expected to provide important modulation of different GABA receptors, (Burgess, K and Ho, K K, J. Am. Chem Soc., 1994, 116, 799-800; Burgess, K. and Li, W, Tetrahedron Lett. , 1995, 16, 2725-2728).
Omega-3 oils or omega-3 fatty acids are naturally occurring, straight-chain (16-24 carbons) fatty carboxylic acids (PUFAs), essential for normal metabolism in humans and other animals. Since the omega-3 fatty acids are not synthesized by the human body, they are recommended to be taken as dietary supplements in 1-4 grams daily for cardiovascular health benefits, preventing strokes, and reducing blood pressure. (Delgado-Lista, J., et al., The British Journal of Nutrition, June 2012, 107 Suppl 2, S201-13).
Omega-3 fatty acids have 3-6 conjugated carbon-carbon double bonds and are so named as the first carbon with unsaturation is 3rd carbon from the distal carboxylic acid carbon. All double bonds are in the cis configuration. Among the omega-3 fatty acids eicosapentanenoic acid (EPA, 20 carbons, 5 conjugated double bonds), docohexaenoic acid (DHA, 22 carbons, 6 conjugated double bonds) and α-linolenic acid (ALA, 18 carbons, 3 conjugated double bonds) are the most studied pharmacologically. The presence of omega-3 fatty acids, especially DHA in the brain is ubiquitous. Clinical studies in 4 year old children support the beneficial effects of docosohexaenoic acid (DHA) on cognitive function (NCT 00351624; 2006-2008; sponsored by Martek BioSciences Corporation). It would be an interesting study to follow such treated children over decades regarding the incidence of onset of symptoms of Alzheimer's disease relative to the untreated group.
Clearly, finding a GABA derivative that has the desired properties of crossing the BBB and provides the desired effects for treatment of neurological conditions is still needed.